Roles of phospholipase D in phorbol myristate acetate-stimulated neutrophil respiratory burst

National Natural Science Foundation of China [39970197, 30971524]; Xiamen University; Ministry of Science and Technology [2009CB522200, 2006AA02A303]The phorbol myristate acetate (PMA) stimulated nutrophil respiratory burst has been considered to simply involve the activation of protein kinase C (PKC). However, the PLD activity was also increased by 10-fold in human neutrophils stimulated with 100 nM PMA. Unexpectedly, U73122, an inhibitor of phospholipase C, was found to significantly inhibit PMA-stimulated respiratory burst in human neutrophils. U73122 at the concentrations, which were sufficient to inhibit the respiratory burst completely, caused partial inhibition of the PLD activity but no inhibition on PKC translocation and activation, suggesting that PLD activity is also required in PMA-stimulated respiratory burst. Using 1-butanol, a PLD substrate, to block phosphatidic acid (PA) generation, the PMA-stimulated neutrophil respiratory burst was also partially inhibited, further indicating that PLD activation, possibly its hydrolytic product PA and diacylglycerol (DAG), is involved in PMA-stimulated respiratory burst. Since GF109203X, an inhibitor of PKC that could completely inhibit the respiratory burst in PMA-stimulated neutrophils, also caused certain suppression of PLD activation, it may suggest that PLD activation in PMA-stimulated neutrophils might be, to some extent, PKC dependent. To further study whether PLD contributes to the PMA stimulated respiratory burst through itself or its hydrolytic product, 1,2-dioctanoyl-sn-glycerol, an analogue of DAG , was used to prime cells at low concentration, and it reversed the inhibition of PMA-stimulated respiratory burst by U73122. The results indicate that U73122 may act as an inhibitor of PLD, and PLD activation is required in PMA-stimulated respiratory burst

Gender Animus Can Still Exist Under Favorable Disparate Impact: a Cautionary Tale from Online P2P Lending

This paper investigates gender discrimination and its underlying drivers on a prominent Chinese online peer-to-peer (P2P) lending platform. While existing studies on P2P lending focus on disparate treatment (DT), DT narrowly recognizes direct discrimination and overlooks indirect and proxy discrimination, providing an incomplete picture. In this work, we measure a broadened discrimination notion called disparate impact (DI), which encompasses any disparity in the loan's funding rate that does not commensurate with the actual return rate. We develop a two-stage predictor substitution approach to estimate DI from observational data. Our findings reveal (i) female borrowers, given identical actual return rates, are 3.97% more likely to receive funding, (ii) at least 37.1% of this DI favoring female is indirect or proxy discrimination, and (iii) DT indeed underestimates the overall female favoritism by 44.6%. However, we also identify the overall female favoritism can be explained by one specific discrimination driver, rational statistical discrimination, wherein investors accurately predict the expected return rate from imperfect observations. Furthermore, female borrowers still require 2% higher expected return rate to secure funding, indicating another driver taste-based discrimination co-exists and is against female. These results altogether tell a cautionary tale: on one hand, P2P lending provides a valuable alternative credit market where the affirmative action to support female naturally emerges from the rational crowd; on the other hand, while the overall discrimination effect (both in terms of DI or DT) favors female, concerning taste-based discrimination can persist and can be obscured by other co-existing discrimination drivers, such as statistical discrimination.Comment: published at FAccT'2

Ecotourism industry in constrained environments: Bhutan as a case study

This chapter analyses the current situation of tourism in Bhutan and discusses the opportunities and challenges of ecotourism in this country. It combines Bhutan’s tourist data, the current tourism policy of the Bhutanese government and the government's measures for culture and environmental protection, exploring the potential development methods to improve and maintain the sustainability of Bhutan's natural and cultural environment by enhancing its ecotourism industry. Furthermore, it also enumerates the adverse effects of over-exploration of tourism in other cities such as Nepal with respect to the importance of ecotourism. A multilayered qualitative research methodology was conducted to determine whether citizens and visitors are in favour of ecotourism activities that might benefit local communities and cultures. It can be concluded that the development of ecotourism is conducive to improving and maintaining the sustainability of Bhutan's natural and cultural environment. Finally, this research ends by providing key recommendations to promote the development of ecotourism to protect Bhutanese people and the country’s Gross National Happiness

Water dissociating on rigid Ni(100): A quantum dynamics study on a full-dimensional potential energy surface

We constructed a nine-dimensional (9D) potential energy surface (PES) for the dissociative chemisorption of H2O on a rigid Ni(100) surface using the neural network method based on roughly 110 000 energies obtained from extensive density functional theory (DFT) calculations. The resulting PES is accurate and smooth, based on the small fitting errors and the good agreement between the fitted PES and the direct DFT calculations. Time dependent wave packet calculations also showed that the PES is very well converged with respect to the fitting procedure. The dissociation probabilities of H2O initially in the ground rovibrational state from 9D quantum dynamics calculations are quite different from the site-specific results from the seven-dimensional (7D) calculations, indicating the importance of full-dimensional quantum dynamics to quantitatively characterize this gas-surface reaction. It is found that the validity of the site-averaging approximation with exact potential holds well, where the site-averaging dissociation probability over 15 fixed impact sites obtained from 7D quantum dynamics calculations can accurately approximate the 9D dissociation probability for H2O in the ground rovibrational state. Published by AIP Publishing

Energy and Delay Optimization of Heterogeneous Multicore Wireless Multimedia Sensor Nodes by Adaptive Genetic-Simulated Annealing Algorithm

Energy efficiency and delay optimization are significant for the proliferation of wireless multimedia sensor network (WMSN). In this article, an energy-efficient, delay-efficient, hardware and software cooptimization platform is researched to minimize the energy cost while guaranteeing the deadline of the real-time WMSN tasks. First, a multicore reconfigurable WMSN hardware platform is designed and implemented. This platform uses both the heterogeneous multicore architecture and the dynamic voltage and frequency scaling (DVFS) technique. By this means, the nodes can adjust the hardware characteristics dynamically in terms of the software run-time contexts. Consequently, the software can be executed more efficiently with less energy cost and shorter execution time. Then, based on this hardware platform, an energy and delay multiobjective optimization algorithm and a DVFS adaption algorithm are investigated. These algorithms aim to search out the global energy optimization solution within the acceptable calculation time and strip the time redundancy in the task executing process. Thus, the energy efficiency of the WMSN node can be improved significantly even under strict constraint of the execution time. Simulation and real-world experiments proved that the proposed approaches can decrease the energy cost by more than 29% compared to the traditional single-core WMSN node. Moreover, the node can react quickly to the time-sensitive events

HSP70 and TNF Loci Polymorphism Associated with the Posner-Schlossman Syndrome in a Southern Chinese Population

Previous studies have shown that HLA gene polymorphisms are associated with the pathogenesis of the Posner-Schlossman syndrome (PSS). This study was aimed at evaluating the associations between HLA-III gene polymorphisms and PSS in a southern Chinese Han population. A total of 150 PSS patients and 183 healthy controls were included in this study. Twenty-one single nucleotide polymorphisms (SNPs) of HLA-III genes (including HSP70-1, HSP70-2, HSP70-hom, TNF-α, TNF-β, C2, and CFB) were genotyped using the SNaPshot technique. Our study showed that the frequencies of G allele at rs909253, A allele at rs1041981, and G allele at rs2844484 of TNF-β in the patient group were significantly higher than those in healthy controls (Corrected P Pc=0.040, OR=1.45; Pc=0.033, OR=1.45; Pc=0.045, OR=1.58, respectively). The frequency of T allele at rs12190359 of HSP70-1 was significantly lower in PSS patients than those in healthy controls (Pc=0.018 and OR=0.10). The frequencies of the CCT haplotype of HSP70-1 gene (rs1008438-rs562047-rs12190359) and the ACCCTTT haplotype of HSP70 gene (rs2227956-rs1043618-rs1008438-rs562047-rs12190359-rs2763979-rs6457452) were significantly lower in PSS patients than those in healthy controls (Pc=0.024, OR=0.10; Pc=0.048, OR=0.10, respectively). In conclusion, the G allele at rs909253, A allele at rs1041981, and G allele at rs2844484 of TNF-β gene might be risk factors for PSS, while the T allele at rs12190359 of HSP70-1 gene and specific haplotypes of the HSP70-1 and HSP70 genes might be protective factors for PSS

PTHrP prevents chondrocyte premature hypertrophy by inducing cyclin-D1-dependent Runx2 and Runx3 phosphorylation, ubiquitylation and proteasomal degradation

In chondrocytes, PTHrP maintains them in a proliferative state and prevents premature hypertrophy. The mechanism by which PTHrP does this is not fully understood. Both Runx2 and Runx3 are required for chondrocyte maturation. We recently demonstrated that cyclin D1 induces Runx2 protein phosphorylation and degradation. In the present studies, we tested the hypothesis that PTHrP regulates both Runx2 and Runx3 protein stability through cyclin D1. We analyzed the effects of cyclin D1 on Runx3 protein stability and function using COS cells, osteoprogenitor C3H10T1/2 cells and chondrogenic RCJ3.1C5.18 cells. We found that cyclin D1 induced Runx3 degradation in a dose-dependent manner and that both Myc-tagged Runx3 and endogenous Runx3 interact directly with CDK4 in COS and RCJ3.1C5.18 cells. A conserved CDK recognition site was identified in the C-terminal region of Runx3 by sequence analysis (residues 356-359). Pulse-chase experiments showed that the mutation of Runx3 at Ser356 to alanine (SA-Runx3) increased the half-life of Runx3. By contrast, the mutation at the same serine residue to glutamic acid (SE-Runx3) accelerated Runx3 degradation. In addition, SA-Runx3 was resistant to cyclin D1-induced degradation. GST-Runx3 was strongly phosphorylated by CDK4 in vitro. By contrast, CDK4 had no effect on the phosphorylation of SA-Runx3. Although both wild-type and SE-Runx3 were ubiquitylated, this was not the case for SA-Runx3. Runx3 degradation by cyclin D1 was completely blocked by the proteasome inhibitor PS1. In C3H10T1/2 cells, SA-Runx3 had a greater effect on reporter activity than SE-Runx3. The same was true for ALP activity in these cells. To investigate the role of cyclin D1 in chondrocyte proliferation and hypertrophy, we analyzed the growth plate morphology and expression of chondrocyte differentiation marker genes in Ccnd1-knockout mice. The proliferating and hypertrophic zones were significantly reduced and expression of chondrocyte differentiation marker genes and ALP activity were enhanced in 2-week-old Ccnd1-knockout mice. PTHrP significantly suppressed protein levels of both Runx2 and Runx3 in primary chondrocytes derived from wild-type mice. By contrast, the suppressive effect of PTHrP on Runx2 and Runx3 protein levels was completely abolished in primary chondrocytes derived from Ccnd1-knockout mice. Our findings demonstrate that the cell cycle proteins cyclin D1 and CDK4 induce Runx2 and Runx3 phosphorylation, ubiquitylation and proteasomal degradation. PTHrP suppresses Runx2 and Runx3 protein levels in chondrocytes through cyclin D1. These results suggest that PTHrP might prevent premature hypertrophy in chondrocytes, at least in part by inducing degradation of Runx2 and Runx3 in a cyclin-D1-dependent manner